DESCRIPTION: (Applicant's Abstract) This application for a NIDA FIRST Award outlines a series of studies designed to examine the involvement of serotonin-lB receptors in the reinforcing and addictive properties of cocaine, and to determine the mechanisms by which these receptors mediate and/or modulate the behavioral effects of this psychostimulant. Cocaine is known to significantly alter serotonin neurotransmission, and chronic cocaine use results in clinical pathologies which are associated with generalized serotonergic dysfunction. However, very little is known about the role of serotonergic neurotransmission in the behavioral effects of cocaine. Recent work indicates that activation of serotonin-lB receptors enhances cocaine reinforcement, though the mechanisms mediating this effect are not known. The first series of experiments will utilize behavioral techniques to determine the neuroanatomical sites which mediate the enhancement in cocaine reward by serotonin-lB receptors (Specific Aim I). It is hypothesized that serotonin-lB receptor activation induces a cascade of neurochemical events involving GABA neurotransmission in the ventral segmental area, basolateral amygdala and sublenticular ventral pallidum, as well as glutamate neurotransmission in the nucleus accumbens, and these events result in an increased activity of the neuronal systems through which cocaine reward is mediated. Thus, a second series of experiments will employ in vivo neurochemical techniques to determine mechanisms by which serotonin-lB receptor stimulation activates brain reward pathways (Specific Aim II). Finally, preliminary evidence indicates that cocaine exposure results in alterations in serotonin-lB receptor function which may contribute to sensitization to the locomotor activating and reinforcing effects of further cocaine intake. A third series of experiments will determine the involvement of serotonin-lB receptors in these long-term effects of cocaine exposure (Specific Aim III). In total, this work will characterize a new link in the circuitry which mediates the reinforcing effects of cocaine. Because the rat serotonin-lB receptor is the homologue of the human serotonin-lD receptor, and these receptors display nearly identical pharmacological profiles, the information gathered from these experiments is likely to have direct relevance to the neurobiological mechanisms of reinforcement in humans. Of equal importance, these studies may identify cocaine-induced alterations in specific brain systems which have significant clinical relevance, thus providing important information for the development of medications for psychostimulant addiction.